Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?
Prospectively enrolled phenylketonuria patients (n=485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN®). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5–20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.
We are indebted to the PKU patients and families who enrolled this study, as well as doctors and their healthcare staff for their invaluable assistance in the conduct of the clinical studies. We also thank our colleagues, John Tomaro for data collection, Sonia Schnieper-Samec for help with statistical review, Kumar Saikatendu and Katya Kadyshevskaya for the 3D figure preparation, Angela Walker for assistance with manuscript preparation and submission to the journal, Sun Sook Kim and Sabrina Cheng for data revision, and Manyphong Phommarinh and Jacques Mao for assistance with PAHdb. A. Gamez was supported by a research contract from “Ramón y Cajal” program by Ministerio de Ciencia e Innovación and Fundación Ramón Areces.
- Burton BK, Grange DK, Milanowski A et al (2007) The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): A phase II, multicentre, open-label, screening study. J Inherit Metab Dis 30(5):700–707PubMedCrossRefGoogle Scholar
- Dobrowolski SF, Borski K, Ellingson CC, Koch R, Levy HL, Naylor EW (2009a) A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. J Hum Genet 54(6):335–339PubMedCrossRefGoogle Scholar
- Donlon J, Levy HL, Scriver CR (2010) Hyperphenylalanine: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW (eds) The metabolic and molecular bases of inherited diseases. McGraw-Hill, New York. Online. http://genetics.accessmedicine.com
- Kure S, Sato K, Fujii K et al (2004) Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 83(1–2):150–156PubMedCrossRefGoogle Scholar
- Panel NIoHCD (2001) National Institutes of Health Consensus Development conference statement: Phenylketonuria: screening and management. Pediatrics 10:972–982Google Scholar
- Trefz FK, Scheible D, Frauendienst-Egger G (2010) Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment. J Inherit Metab Dis Mar 9 EpubGoogle Scholar
- Waters PJ, Parniak MA, Akerman BR, Scriver CR (2000) Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype. Mol Genet Metab 69(2):101–110PubMedCrossRefGoogle Scholar